5(3-Substituted aminopropyl)-10-trifluoromethoxy-5H-dibenz[b,f]azepines

ABSTRACT

Novel compounds of general formula ##STR1## (where R 1  and R 2 , which may be the same or different, are hydrogen atoms or alkyl groups; and R 3  and R 4 , which may be the same or different, represent alkyl groups which may carry substituents, R 4  alternatively representing a hydrogen atom; or R 3  and R 4  together with the intervening N represent a heterocyclic group or an acid-addition salt thereof) are provided, together with a process for their preparation. The new compounds are useful as antidepressants.

This is a continuation, of application Ser. No. 500,189, filed Aug. 23,1974, now abandoned.

This invention relates to novel dibenzazepines related to imipraminewhich have notable anti-depressant activity.

The new compounds are characterised in having a 10-Trifluoromethoxysubstituent and a 10,11-double bond together with the 5-side chain andother nuclear substituents of imipramine and its analogues, and are thus5-(3'-aminoprop-1'-yl)-10-trifluoromethoxy-5H-dibenz[b,f]azepines.

The compounds according to the present invention may, in general, berepresented by the formula ##STR2## where R¹ and R² which may be thesame or different are hydrogen atoms or alkyl groups; and

R³ and R⁴ which may be the same or different represent alkyl groupswhich may carry substitutents such as aryl groups, e.g. phenyl groups,or alkylamino groups, e.g. diethylamino or dimethylamino groups, R⁴alternatively representing a hydrogen atom; or R³ and R⁴ together withthe intervening N represent a heterocyclic group. The nucleus may alsooptionally carry further substituents such as alkyl, alkoxy, oralkylthic groups or halogen atoms; and acid addition salts thereof.

R³ and R⁴ are preferably lower alkyl groups, e.g. with 1-6 carbon atomssuch as methyl, ethyl, propyl, butyl, isopropyl, or hexyl groups,optionally carrying an aryl substituent, as in the benzyl or phenethylgroups, or a dialkylamino group such as a 2-diethylamino-ethyl or2-dimethylaminoethyl group.

R³ and R⁴ together with the intervening N may represent a heterocyclicgroup such as a cyclic amine with 5 to 8 ring members, optionallycontaining further heteratoms. R³ and R⁴ may thus, for example, comprisea cyclic monoamine group such as a piperidine, pyrrolidine,hexamethylenimine or morpholine group or a cyclic diamine group such asa piperazine, N-alkylpiperazine or N-hydroxyalkylpiperazine, e.g.N-hydroxyethyl piperazine group.

R¹ and R² preferably represent hydrogen atoms or lower alkyl groups,e.g. with 1-6 carbon atoms, such as methyl groups.

The acid addition salts may be salts with mineral acids, e.g.hydrochloric, hydrobromic or sulphuric acid, or organic acids, e.g.maleic or tartaric acid.

Nuclear substituents which may be present include halogen atoms,especially chlorine atoms; alkyl groups such as methyl groups, alkoxygroups such as methoxy or ethoxy groups or alkylthio groups such asmethylthio, ethylthio or isopropylthio groups. Such substituents arepreferably in one or more of the 2-, 3-, 7- and 8-postions, for example,2-chloro, 3-chloro, 7-chloro, 8-chloro, 3,7-dichloro, 2-methoxy or3-methylthio substituents. The alkyl, alkoxy and alkyl groups preferablycontain 1-6 carbon atoms.

The compounds according to the present invention preferably carry a5-(3-dimethylaminopropyl)-side chain as in the preferred compound5-(3-dimethylaminopropyl)-10-trifluoromethoxy-5H-dibenz[b,f]azepine.

The compounds exhibit notable anti-depressant activity and particularlylow CNS side-effects, which renders them of particular interest in thetreatment of depression states, in particular endogenous depression.Thus, the new compounds are tolerated at substantially higher doses thanthe related compound iminpramine, and being approximately equallyactive, so have an improved therapeutic ratio.

According to the further feature of the present invention we providepharmaceutical compositions comprising a compound of the general formulaI as defined above together with a pharmaceutical carrier or excipient.Suitable forms include the usual types of anti-depressant formulationusing especially the oral route, for example, tablets, coated tablets,capsules, syrups and elixirs. Formulations for injection may also beused. The compositions are preferably dosage unit forms, in particulartablets and coated tablets. Each dosage unit preferably contains 2.5 to300 mg, advantageously 10 to 50 mg, especially 15-20 mg of activeingredient.

The compounds of general formula I may, in general, be prepared by theaddition of trifluoromethyl hypofluorite across the 10,11-double bond ofa 5-acyl-5H-dibenz[b,f]azepine using the method of British PatentSpecification No. 1,244,642 to give a CF₃ OF adduct which on treatmentto eliminate HF and the 5-acyl group gives an intermediate10-trifluoromethoxy-5H-dibenz[b,f]azepine which may be reacted tointroduce the appropriate 5-substituent.

According to a further feature of the present invention we provide aprocess for the preparation of a compound of the general formula I asdefined above in which 10-trifluoromethoxy-5H-dibenz[b,f]azepine, i.e. acompound of the general formula ##STR3## (where the nucleus may carrysubstituents) or an N-alkali metal derivative thereof is reacted with analkylating reagent serving to introduce a 3-substituted prop-1-yl e.g. agroup of the formula ##STR4## where R¹ and R² are as defined above andR⁷ is a group --NR³ R⁴ where R³ and R⁴ are as defined above, or asubstitutent convertible into a group --NR³ R⁴.

The alkylating reagent may conveniently be of the formula ##STR5## whereX represents a reactive ester radical such as a halogen atom or analkane sulphonyloxy or arylsulphonyloxy group, and R¹, R² and R⁷ havethe above meanings. The reaction is preferably effected in an aproticsolvent of high dielectric constant such as an ether, e.g. dimethylether, diethyl ether or tetrahydrofuran. A substituent convertible intoa group --NR³ R⁴ may, for example, be --NH₂ which may subsequently bealkylated, or a halogen atom (less reactive than X) which maysubsequently be reacted with an amino NR³ R⁴.

The reagent of formula II is preferably used in the form of an alkalimetal derivative such as a sodium or potassium, derivative and such ametallated derivative may conveniently be obtained by reacting acompound of formula II in the NH form with a metallating agent such asan alkali metal hydride or alkyl.

An alternative process for the preparation of compounds of the generalformula I as defined above comprises the reaction of a compound of thegeneral formula ##STR6## where R¹, R², R³, R⁴ and the optional nuclearsubstituents are as defined above, with a reagent serving to reduce anamide to an amine, e.g. a lithium aluminium hydride, diborane or theBouveault-Blanc reagent.

The compounds of the general formula II may be obtained by reaction of a5-acyl-5H-dibenz[b,f]azepine of the general formula ##STR7## where Acrepresents an acyl group, in particular a group --COR⁵, where R⁵represents an alkyl, haloalkyl, aminoalkyl, alkoxy or aralkoxy group ora halogen atom and where the nucleus may carry substituents, withtrifluoromethyl hypofluorite to form an intermediate of the generalformula ##STR8## (where Ac is as defined above and the nucleus may carrysubstituents) which is subsequently reacted with a reagent serving toremove HF.

The reaction with the hypofluorite reagent initially yields a mixture ofcis and trans isomers at the 9- and 10-positions but elimination of HFregenerates the 9,10-double bond in both isomers so that no separationis required, although the individual isomers can readily be isolatede.g. by chromatography or fractional crystallisation.

It will be seen that where Ac represents a group of the formula --COCHR¹CHR² NR³ R⁴, the product obtained is of the formula IV defined above.The acyl derivative of formula VI constitute important intermediates andare thus a further feature of the invention.

The acyl group may be removed, conveniently at the same time as the HF,by treatment under the appropriate conditions, although the HF may beeliminated while leaving the acyl group in position if a compound offormula IV is required. The halocarbonyl or alkoxycarbonyl group isparticularly easy to remove by standard methods.

The reagent serving to remove HF may conveniently comprise an amine or ametal halide, hydroxide or alkoxide. For simultaneous removal of theacyl group stronger conditions should be chosen, for example, treatmentwith an alcoholic alkali metal hydroxide at elevated temperatures.

The following Examples illustrate the invention.

PREPARATION 1 N-Acetyl iminostilbene, (5-Acetal-5H-dibenz[b,f]azepine)

Iminostilbene(2 g) was added to a mixture of Ac₂ O/pyridine 2:1(5 ml)and the solution was refluxed for 3 hours after which the solution waspoured into water (100 ml) and the precipitate filtered off. Thisprecipitate was purified by chromatography on silica gel eluted withchloroform to give the product as colourless needles, mp. 120°-121° C.(lit. 121°-122° C.); yield 2 g.

PMR: 7.4 (8Hm), 6.9(2Hs), 1.8(3Hs).

IR(KRr): ν_(max) 1680 cm⁻¹

UV(MeOH) λ_(max) =285 mμ (ε=12,900).

PREPARATION 2 N-Ethoxycarbonyliminostilbene,(5-ethoxycarbonyl-5H-dibenz[b,f]azepine)

Iminostilbene (4 g) was added to sodium-dried toluene (300 ml)containing NaH(1 g.) The mixture was refluxed for 4 hours, after whichthe solution was a deep black colour. Ethyl chloroformate (3 ml) wasslowly added until the black colour had disappeared. After the solutionhad cooled, the remaining NaH was destroyed by the slow addition ofmethanol. The solution was filtered and the residue washed withchloroform (50 ml). The toluene and chloroform solutions were combinedand the solvent removed under vacuum. The resulting solid was dissolvedin boiling hexane (200 ml) and the product (5 g) crystallised out oncooling:

colourless needles; mp 130°-131° C. (lit, 126°-128° C.).

IR(KBr)ν_(max) =1700 cm⁻¹.

PMR. 7.4 (8Hm) 6.90(2Hs) 4.10(2Hq.J=7 Hz) 1.12(3Htr.J=7 Hz)

UV(MeOH)λ_(max) =283 (ε=10,000), 233 (ε=15,800).

PREPARATION 3 Addition of trifluoromethyl hypofluorite to the productsof Preparations 1 and 2

10 millimoles of the iminostilbene derivative were dissolved in 200 mls.of solvent containing CaO(0.5 g). The solution was cooled to -78° C. ina methylene chloride/dry ice bath with stirring. CF₃ OF (300 ml ca. 70%pure) was bubbled into the solution via a water wash and a trap cooledto -78° C. The rate of addition was ca. 10 ml/min. The solution was thenflushed with nitrogen for 20 min, brought to room temperature, washedwith dilute aqueous sodium bicarbonate, dried over sodium sulphate andthe solvent removed under vacuum. The resulting oil was then eitherchromatographed repeatedly on alumina or silica, or in the case of theN-ethoxycarbonyl adducts, crystallised from hexane. Yields ca.95%.

(a) N-acetyl-iminostilbene:

trans CF₃ OF adduct: m.p. 100°-103° C. colourless crystals, mixed mp.with cis adduct less than 90° C.

IR ν_(max) =1670, 1160-1270 cm⁻¹

M⁺ :339.03 C₁₇ H₁₃ F₄ NO₂ requires 330.0

PMR: δ7.5(8Hm), δ5.0-6.8)2Hm), δ2.2(3Hm).

cis CF₃ OF adduct: mp. 114-116C, colourless crystals.

IR: ν_(max) =1670, 1160-1270 cm⁻¹

M⁺ =339.03

PMR. δ7.5(8HM), δ6.2-5.0(2Hm).δ2.0(3Hs)

Microanalysis:

C₁₇ H₁₃ F₄ NO₂ requires: C 60.2%; H 3.84%; F 22.4%.

found for trans: C 60.21%; H 3.92%; F 22.22%; cis: C 60.17%; H 3.94%.

(b) N-Ethoxycarbonyl-iminostilbene

trans CF₃ OF adduct: colourless needles, mp. 107°-107.5° C.

IR (KBr): ν_(max) =1710 cm⁻¹ (s), 1100-1300 cm⁻¹ (s)

UV(MeOH) ν_(max) =268 (ε=1100), 235sh (ε=6960)

PMR: δ7.3(8Hm), δ6.3-δ4.8(2Hm), δ4.2(2Hq,J=7 Hz), δ1.2(3Htr.J=7 Hz)

FMR: φ*+67.2 and +68.8 ppm (two br.s.1:2, 3F) +180 (br.q.J=50,13 Hz)+206 (br.s.) (1F)

cis CF₃ OF adduct; colourless rosettes of needles, mp. 133°-34° C. mmpwith trans 90°-94° C.

UV(MeOH) 263(1000) 229sh(7830)

IR(KBr) 1705 cm⁻¹ (s) 1150-1300 cm⁻¹ (s)

PMR. δ7.4(8HM)δ6.5-5.3(2H, four br.s.)δ4.2(2Hq.,J=7 Hz)δ1.2 (3Htr. J=7Hz.)

Fmr φ*+68.8,70.8(3F, two br.s.) +201-202.6(1F, four br.s)

Microanalysis. C₁₈ H₁₅ F₄ NO₃ requires, C 58.54%, H4.09%, F 20.58% N3.79%.

Found for trans, C58.59%, H4.25%, F20.26%, N3.78%.

cis, C58.09%, H4.08%, F20.90%, N3.65%.

cis fluoromethoxy adduct, isolated in up to 50% yield on fluorination inmethanol, colourless rosettes of needles, m.p. 101°-102° C. corr.

IR(KBr) ν_(C=0) 1705 cm⁻¹

UV(MeOH) 267(890) 230sh(7840)

PMR. δ7.7-δ7.2(8Hm), [δ6.3 brs., δ5.5 brs., δ5.2 brs.) δ4.7d](OH)

δ4.2(2HqJ=7 Hz), δ3.6(3H Br.s.), δ1.2(3H br., J=7 Hz).

FMR. φ*202 ppm (br., J=25 Hz).

Microanalysis C₁₈ H₁₈ FNO₃ requires, C68.56%, H5.75%, F6.02%, N4.44%.

Found: C68.55%, H5.70%, F6.23%, N4.40%.

PREPARATION 4 Elimination of HF with base

N-ethoxycarbonyl iminostilbene (2.92 g) was allowed to react with CF₃ OF(400 ml) in methylene chloride. The solvent was removed under vacuum andthe remaining gum was dissolved in EtOH (150 ml) to which KOH (20 g) wasadded with stirring. The solution was refluxed overnight and the solventwas then removed under vacuum. The product was extracted from theresidue with benzene (100 ml) and the benzene extract was washed withwater (2×25 ml) and dried over magnesium sulphate. The solution wasconcentrated to 10 ml and chromatographed on silica (100 g) eluting withbenzene/hexane (2:3). The fractions were examined by glc. (1.5%NGS; 200°C.) and it was found that 10-trifluoromethoxy iminostilbene(10-trifluoromethoxy-5H-dibenz[b,f]azepine was eluted first, yield 1.94g (73%), as a yellow crystalline solid mp. 61°-62° C.

IR (KBr & CHCl₃ solution): ν_(max) =3400 cm⁻¹ w. 1220,1250 cm⁻¹ s.

PMR: 7.4-6.3(9Hm) 4.97(1H br.s.)

UV(MeOH): ν_(max) =255 (ε=39,600), 292sh (ε=3,680)

microanalysis:

C₁₅ H₁₀ F₃ NO requires, C, 64.98%, H3.61%, F,20.58%, N,5.05%.

Found C, 64.97%, H3.44%, F,20.31%, N,4.98%.

The remaining fractions contained both 10-fluoro-iminostilbene and10-trifluoromethoxy-iminostilbene. The 10-fluoro product was isolatedtolerably pure (100 mg) as a yellow crystalline solid mp. 74°-76° C.

IR(KBr) ν_(max) =3450 cm⁻¹ w., 1060 cm⁻¹ s.

PMR: 7.4-6.4 (8Hm) 6.22(1Hd,J=20 Hz) 5.1(1H br.s)

no satisfactory analysis was obtained.

EXAMPLE 15-(3-Dimethylaminopropyl)-10-trifluoromethoxy-5H-dibenz[b,f]azepine

10-Trifluoromethoxy-5H-dibenz[b,f]azepine (650 mg) was refluxed with NaH(600 mg, 57% suspension) in a solution of 3-dimethylaminopropyl chloride(ca. 2.0 g) in dimethyl ether (70 ml) overnight. The excess of NaH wasdestroyed with MeOH (10 ml) and the solvent removed under vacuum. Theremaining gum was dissolved in ether (50 ml), washed with water (2×20ml) and extracted into 2 N H₂ SO₄ (2×20 ml). The extracts were combined,neutralized with NaHCO₃ and extracted with ether (3×20 mls). The etherextracts were washed with water (2×20 mls), dried (Na₂ SO₄) and theether removed under vacuum.

Yield 775 mg (95%) of a yellow oil. b.p. 90° at 80 torr.; n_(D) ²⁶=1.5525

UV(MeOH): λ_(max) 254 (ε=26820), 281 (ε=3800), 347 (ε=480).

PMR: δ7.6-δ7.0(8Hm), δ6.9 (1H br.tr.1/2 to =4 Hz), δ3.8 (2H br.tr., J=7Hz), δ2.4(2H br.tr., J=7 Hz) δ8.20 (6Hs), δ1.7 (2Hm).

IR (CCl₄): λ_(max) =1170, 1230 cm⁻¹ (s) (OCF₃).

    ______________________________________                                        microanalysis:  C       H       F     N                                       ______________________________________                                        C.sub.20 H.sub.21 F.sub.3 N.sub.2 O requires:                                                 66.28   5.84    15.73 7.73%                                   Found:          66.10   5.78    15.92 7.49%                                   ______________________________________                                    

The free base was dissolved in ethanol and the solution treated with anethanol solution of hydrogen chloride, followed by addition of ether toinduce crystallisation of the hydrochloride salt so formed.

The corresponding maleate and tartrate salts were prepared similarly,using ethanol solutions of maleic and tartaric acid respectively.

EXAMPLE 2 Tablets

Composition:

1 tablets contains

    ______________________________________                                        5-(3-dimethylaminopropyl)10-trifluoromethoxy-                                 5H-dibenz[b,f]azepine hydrochloride                                                                        10.00 mg                                         lactose                      35.0 mg                                          potato starch                49.0 mg                                          polyvinyl pyrrolidone        5.0 mg                                           magnesium stearate           1.0 mg                                                                       100.0 mg                                          ______________________________________                                    

EXAMPLE 3 Coated Tablets

Composition:

1 tablet core contains

    ______________________________________                                        5-(3-dimethylaminopropyl)-10-trifluoromethoxy-                                5H-dibenz[b,f]azepine hydrochloride                                                                       25.0 mg                                           lactose                     35.0 mg                                           polyvinyl pyrrolidone        6.0 mg                                           corn starch                 13.0 mg                                           magnesium stearate           1.0 mg                                                                       80.0 mg                                           ______________________________________                                    

Tablets cores of this composition are coated with sugar and talcum andwax polished to give finished tablets of 120.0 mg.

EXAMPLE 4 Capsules

Capsules containing the same active ingredient as Examples 2 and 3 areprepared by mixing the active ingredient (20.0 mg per capsule) andlactose (80.0 mg per capsule) and filling standard gelatin 100 mg sizecapsules.

EXAMPLE 5 Ampoules for Intramuscular Injection

Each ampoule contains:

    ______________________________________                                        5-(3-dimethylaminopropyl)-10-trifluoromethoxy-                                5H-dibenz[b,f]-azepine hydrochloride                                                                      10.0 mg                                           Ascorbic acid               0.5 mg                                            Sodium bisulphite           0.5 mg                                            Sodium sulphite             1.0 mg                                            Water for injection                                                                          ad               2.0 ml                                        ______________________________________                                    

We claim:
 1. A compound of the formula: ##STR9## wherein R¹ and R² whichmay be the same or different are hydrogen atom or C₁₋₆ alkyl groups; andR³ and R⁴ which may be the same or different represent C₁₋₆ alkyl groupswhich may carry as substituents phenyl or di-C₁₋₆ alkylamino groups, R⁴alternatively representing a hydrogen atom; the nucleus of said compoundmay be unsubstituted or carry at least one substituent selected from thegroup consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio and halogenatoms; or a physiologically acceptable acid addition salt thereof.
 2. Acompound as claimed in claim 1, in which R¹ and R² represent hydrogenatoms R³ represents a methyl group and R⁴ represents a methyl group or ahydrogen atom.
 3. A compound as claimed in claim 2 namely5-(3-dimethylaminopropyl)-10-trifluoromethoxy-5H-dibenz[b,f] azepine ora physiologically acceptable acid addition salt thereof.
 4. The compoundof claim 1, wherein the nucleus carries a further substituent selectedfrom the group consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio andhalogen atoms.
 5. A compound as claimed in claim 1, wherein the acidaddition salt is formed from hydrochloric, hydrobromic, sulphuric,maleic or tartaric acid.
 6. A compound as claimed in claim 4, whereinthe substituents on the nucleus are substituted in one or more of the2-, 3-, 7- and 8-positions.
 7. A compound as claimed in claim 6, whereinthe substituents are 2-chloro, 3-chloro, 7-chloro, 8-chloro,3,7-dichloro, 2-methoxy or 3-methylthio substituents.